Is BRAF p.Ser394Pro (c.1180T>C) pathogenic?

BRAF p.Ser394Pro (c.1180T>C) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0913); Very rare (popmax 0.0011%, nfe); Associated with Noonan syndrome 1.

What condition is associated with BRAF p.Ser394Pro (c.1180T>C)?

BRAF p.Ser394Pro (c.1180T>C) is associated with Noonan syndrome 1, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Ser394Pro (c.1180T>C) in the general population?

BRAF p.Ser394Pro (c.1180T>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Ser394Pro (c.1180T>C)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

BRAF p.Ser394Pro

c.1180T>C · rs923739321 · VCV910575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Noonan syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 3.5, phastCons 1
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,952 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,902 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BRAF
Protein: p.Ser394Pro
Coding: c.1180T>C
MANE Select: NM_004333
dbSNP: rs923739321
Type: single nucleotide variant
Location: chr7:140783155 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 394: the 'disordered' region

Full BRAF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Noonan syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer cardiofaciocutaneous syndrome 1 melanoma, cutaneous malignant, susceptibility to, 1 lung cancer Noonan syndrome 7 LEOPARD syndrome 3 RASopathy

Similar variants

BRAF p.Ser394Ala Uncertain significance ★ ⚠ same residue
BRAF p.Ser394= Likely benign ★ same residue
BRAF p.Ala246Pro Pathogenic ★★★ same condition
BRAF p.Asn581Asp Pathogenic ★★★ same condition
BRAF p.Asp594Val Pathogenic ★★★ same condition
BRAF p.Cys532Tyr Likely pathogenic ★★★ same condition
BRAF p.Gln257Arg Pathogenic ★★★ same condition
BRAF p.Gly265Arg Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/braf-p-ser394pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown